This proposal describes a 5-year plan for the development of an academic career in epigenetics, mouse and human cell-based modeling of disease, and cancer biology. This training period will complement my training in molecular and clinical genetics. Dr. Marisa Bartolomei, a renowned expert in epigenetics and mouse models, and Dr. Garrett Brodeur, an international authority in cancer biology, will mentor my scientific and career development. To facilitate my scientific development, I have assembled an advisory committee including an eminent human geneticist and two prominent cancer biologists. My research focuses on tumor formation in Beckwith-Wiedemann syndrome (BWS). BWS is an overgrowth and tumor predisposition disorder that affects at least 1 in 13,700 children. Many of these children develop cancer, most commonly hepatoblastomas and Wilms tumors. BWS is part of a spectrum of clinical disease ranging from classic features of generalized overgrowth to subtle isolated overgrowth of a single limb or organ. My previous work demonstrated that even patients with subtle BWS features develop tumors. BWS is caused by genetic and/or epigenetic changes on chromosome 11. Similar changes occur in a number of cancers including breast and colon cancer. Studying BWS presents a unique opportunity to study a rare disorder in order to provide insight into common tumor formation pathways. In this proposal, we will use our BWS patient cohort of over 250 patients to identify subtle clinical features predictive of increased tumor risk. Using fibroblast samples collected from these patients, we are developing the first human cell-based models of BWS using induced pluripotent stem cells (iPSCs). The iPSCs will be differentiated into the cell lineages in which tumors develop (e.g. hepatocytes) and global molecular profiling will be performed to identify pathways involved in tumorigenesis. Finally, we have designed a novel mouse model to specifically look at the independent role of two of the genes on chromosome 11 (H19 and miR675) in growth and tumor formation. The completion of the proposed studies will improve tumor risk assessment in BWS patients and define the pathways leading to tumor formation in these patients. This work is a necessary first step towards improving the care of children with BWS by identifying new potential tumor screening modalities and therapeutic targets. Additionally, this patient cohort and these models will provide an invaluable resource for my career endeavors.